Exchangeable apolipoproteins are essential structural and functional components of lipoproteins. The stability of the lipoprotein particles, the activity of lipolytic enzymes and lipid transfer proteins, and the binding of the lipoprotein to receptors are among the processes regulated by the properties of apolipoproteins, which bind to the lipoprotein lipid surfaces as well as to cell membranes. Apolipoproteins modulate all those 3rocesses by means of their lipid binding activity, rate and extent of binding, and their structure in the lipid-bound state. Therefore, the molecular properties of the exchangeable apolipoproteins define the physiological role of lipoproteins and the homeostasis of the lipid metabolism, in general. The understanding of the physiological role of a given apoLp depends on the knowledge of the structure and properties of the protein molecule in both the soluble and lipid-bound state(s). The long-term goals of this project are the lentification and characterization of the functional domains of apolipoproteins in the lipid-bound states. This proposal involves studies on the relationship between structure and function of two apolipoproteins: insect ,Apolipophorin-Ill and human apolipoprotein A-I. The specific aims of this proposal include: 1) Study of the organization of apoA-I molecules in discoidal HDL iipoproteins; 2) The study of the regions of human apoA-I that interact with lipid in high-density lipoproteins; 3) The study of the correlation between the structure of apoA-I in HDL particles and the function of the lipoproteins. 4) The study of the mechanism of association of apolipophorin-III with phospholipid monolayers and bilayers, including native lipoproteins and reconstituted model lipoproteins; Accomplishment of these objectives is necessary to fully understand the physiology and pathology of the metabolic pathways where apolipoproteins are involved. This includes understanding of the role of apolipoproteins in the metabolism of lipids and related pathologies, such as atherosclerosis, but it could also involve other kind of pathologies, such as Alzheimer's disease.